Voltage-gated calcium channels mediate calcium entry into neurons and regulate firing patterns, neurotransmitter release, gene expression, and differentiation. They have been classified as L-, N-, P/Q-, R and T-type according to their electrophysiological and pharmacological properties (Dunlap et al., 1995). There has been extensive research into the role of L-type calcium channels in mediating the behavioral effects of ethanol, driven largely by the widespread availability of high affinity antagonists for these channels (Little, 1995). For example, the dihydropyridine nimodipine inhibits both the acquisition and expression of ethanol self-administration (De Beun et al., 1996; Kuzmin et al., 1999) and prevents the inhibitory effects of ethanol on memory in radial arm maze and object recognition tests (Brooks et al., 2002). L-type channel antagonists also reduce alcohol withdrawal seizures in rodents (Watson and Little, 1999).
N-type calcium channels are multimeric complexes containing at least three kinds of subunits. Two of these, β and α2δ are also found in all neuronal voltage-gated calcium channels. The third kind of subunit, α1 is unique for each type of calcium channel, and Cav2.2 α1, is unique for the N-type calcium channel.
Ethanol has been shown to increase the level of N-type calcium channels by a protein kinase Cε (PKCε)-mediated mechanism. McMahon et al. (2000) Mol. Pharm. 57:53-58. Brief exposure to ethanol (Solem et al. (1997) J. Pharmacol. Exp. Ther. 282:1487-95), opiates (Soldo and Moises (1997) Brain Res. 758:118-126), or cannabinoids (Mackie and Hille (1992) Proc. Natl. Acad. Sci., USA 89:3825-29) inhibits N-type channels.
Despite the cellular and molecular data indicating that ethanol modulates N-type calcium channels, it was not known whether this interaction contributed to the behavioral effects of ethanol. This question was addressed using a genetic approach, i.e., by studying ethanol responses in mice that carry a null mutation in the calcium channel subunit Cav2.2 and, therefore, lack functional N-type calcium channels (Kim et al., 2001). Cav2.2 null mice develop normally with no overt phenotypic abnormalities. In dorsal root ganglion cultures from Cav2.2 null mice, the level of L-, P/Q- and R-type calcium channel currents are unchanged compared to wild-type neurons, indicating a selective absence of N-type channel activity that does not alter the function of remaining voltage-gated calcium channels (Kim et al., 2001).